The transition from an in utero environment to life outside the womb is marked by a change from a relatively hypoxic environment (<3% oxygen) to a more oxidative atmospheric environment (21% oxygen). Lungs of prematurely born infants are underdeveloped with fewer alveoli and relatively lower expression of antioxidant enzymes. Consequently, premature infants are at a disadvantage in coping with this oxidative transition, even before therapeutic interventions such as supplemental oxygen (hyperoxia) and mechanical ventilation are considered. Bronchopulmonary dysplasia (BPD) is one possible result of sustained oxygen supplementation in premature infants, which is marked by alveolar simplification, pulmonary hypertension, and dysmorphic vascular growth. BPD adversely affects long-term lung function as evidenced by enhanced susceptibility to respiratory infection and development of an asthmatic-type syndrome. Thus, there is an urgent need to understand how oxygen tension regulates alveolar epithelial development and how environmental alterations result in newborn disease pathologies. Thiol modifications have been shown to play a major role in redox signaling pathways by regulating protein activity and are known to contribute to pulmonary disease pathologies. Thioredoxin-1 (Trxl) is a redox-sensitive protein containing a dithioldisulfide site responsible for oxidoreductase activity, making it a unique regulator of redox homeostasis since it can directly transcribe changes in oxygen tension (such as during birth or newborn oxidative injury) into developmental pathways by modifying thiol redox status. Therefore, we will test the hypothesis that newborn oxygen alters alveolar growth and development via Trx1. Goals of the proposed studies are to: 1) investigate redox proteomics of the nuclear compartment during hyperoxic injury;2) examine how Trx1 regulates alveolar development during neonatal hyperoxia;and, 3) identify Trx1-dependent redox-sensitive signaling pathways altered during hyperoxic treatment. By identifying cellular mechanisms underlying redoxdependent changes in pulmonary epithelial growth, we will develop innovate strategies designed to improve children's health.

Public Health Relevance

By identifying redox-sensitive molecular networks during alveolar growth, these studies will enhance our understanding of redox switches during pulmonary development. These pathways could lead to the development of novel therapeutics for BPD and provide a cellular basis for treating other disease pathologies elicited by oxidative injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
1P20GM103620-01A1
Application #
8465612
Study Section
Special Emphasis Panel (ZGM1-TWD-B (CB))
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$295,072
Indirect Cost
$110,652
Name
Sanford Research/Usd
Department
Type
DUNS #
050113252
City
Sioux Falls
State
SD
Country
United States
Zip Code
57104
Forred, Benjamin J; Neuharth, Skyla; Kim, Dae In et al. (2016) Identification of Redox and Glucose-Dependent Txnip Protein Interactions. Oxid Med Cell Longev 2016:5829063
Rickel, Kirby; Fang, Fang; Tao, Jianning (2016) Molecular genetics of osteosarcoma. Bone :
Kim, Dae In; Jensen, Samuel C; Noble, Kyle A et al. (2016) An improved smaller biotin ligase for BioID proximity labeling. Mol Biol Cell 27:1188-96
White, Katherine A; Hutton, Scott R; Weimer, Jill M et al. (2016) Diet-induced obesity prolongs neuroinflammation and recruits CCR2(+) monocytes to the brain following herpes simplex virus (HSV)-1 latency in mice. Brain Behav Immun 57:68-78
Simpkins, Jessica A; Rickel, Kirby E; Madeo, Marianna et al. (2016) Disruption of a cystine transporter downregulates expression of genes involved in sulfur regulation and cellular respiration. Biol Open 5:689-97
Booze, Michelle L; Hansen, Jason M; Vitiello, Peter F (2016) A novel mouse model for the identification of thioredoxin-1 protein interactions. Free Radic Biol Med 99:533-543
Yao, Qingqing; Liu, Yangxi; Tao, Jianning et al. (2016) Hypoxia-mimicking nanofibrous scaffolds promote endogenous bone regeneration. ACS Appl Mater Interfaces :
Alam, Samer G; Zhang, Qiao; Prasad, Nripesh et al. (2016) The mammalian LINC complex regulates genome transcriptional responses to substrate rigidity. Sci Rep 6:38063
Mdaki, Kennedy S; Larsen, Tricia D; Wachal, Angela L et al. (2016) Maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancy through metabolic stress and mitochondrial dysfunction. Am J Physiol Heart Circ Physiol 310:H681-92
Baack, Michelle L; Puumala, Susan E; Messier, Stephen E et al. (2016) Daily Enteral DHA Supplementation Alleviates Deficiency in Premature Infants. Lipids 51:423-33

Showing the most recent 10 out of 30 publications